tbuckley/cabot-search huggingface dataset:
Long-Term Exposure to Ambient Air Pollution and Mortality among Four Million COVID-19 Cases in Italy: The EpiCovAir Study
Authors: Massimo Stafoggia, Andrea Ranzi, Carla Ancona, Lisa Bauleo, Antonino Bella, Giorgio Cattani, Federica Nobile, Patrizio Pezzotti, Ivano Iavarone
Journal: Environmental Health Perspectives (2023)

Background: The role of chronic exposure to ambient air pollutants in increasing COVID-19 fatality is still unclear. Objectives: The study aimed to investigate the association between long-term exposure to air pollutants and mortality among 4 million COVID-19 cases in Italy. Methods: We obtained individual records of all COVID-19 cases identified in Italy from February 2020 to June 2021. We assigned 2016–2019 mean concentrations of particulate matter (PM) with aerodynamic diameter ≤10μm (PM10), PM with aerodynamic diameter ≤2.5μm (PM2.5), and nitrogen dioxide (NO2) to each municipality (n=7,800) as estimates of chronic exposures. We applied a principal component analysis (PCA) and a generalized propensity score (GPS) approach to an extensive list of area-level covariates to account for major determinants of the spatial distribution of COVID-19 case–fatality rates. Then, we applied generalized negative binomial models matched on GPS, age, sex, province, and month. As additional analyses, we fit separate models by pandemic periods, age, and sex; we quantified the numbers of COVID-19 deaths attributable to exceedances in annual air pollutant concentrations above predefined thresholds; and we explored associations between air pollution and alternative outcomes of COVID-19 severity, namely hospitalizations or accesses to intensive care units. Results: We analyzed 3,995,202 COVID-19 cases, which generated 124,346 deaths. Overall, case–fatality rates increased by 0.7% [95% confidence interval (CI): 0.5%, 0.9%], 0.3% (95% CI: 0.2%, 0.5%), and 0.6% (95% CI: 0.5%, 0.8%) per 1 μg/m3 increment in PM2.5, PM10, and NO2, respectively. Associations were higher among elderly subjects and during the first (February 2020–June 2020) and the third (December 2020–June 2021) pandemic waves. We estimated ∼8% COVID-19 deaths were attributable to pollutant levels above the World Health Organization 2021 air quality guidelines. Discussion: We found suggestive evidence of an association between long-term exposure to ambient air pollutants with mortality among 4 million COVID-19 cases in Italy. https://doi.org/10.1289/EHP11882
Nigeria’s marathon struggle against counterfeit medicines
Authors: Oluwatosin Adeshokan, Christine Ro
Journal: BMJ (2023)

Counterfeit and substandard medicines are not unusual in Africa. A concerted enforcement effort and reworked regulation have lessened the problem in Nigeria—but the roots remain, report <b>Oluwatosin Adeshokan</b> and <b>Christine Ro</b>
Transcriptional programming of CD4 <sup>+</sup> T <sub>RM</sub> differentiation in viral infection balances effector- and memory-associated gene expression
Authors: Quynh P. Nguyen, Kennidy K. Takehara, Tianda Z. Deng, Shannon O’Shea, Maximilian Heeg, Kyla D. Omilusik, J. Justin Milner, Sara Quon, Matthew E. Pipkin, Jinyong Choi, Shane Crotty, Ananda W. Goldrath
Journal: Science Immunology (2023)

After resolution of infection, T cells differentiate into long-lived memory cells that recirculate through secondary lymphoid organs or establish residence in tissues. In contrast to CD8
Clinical development of new drugs for adults and children with cancer, 2010-2020
Authors: Andrea Arfè, Claire Narang, Steven G DuBois, Gregory Reaman, Florence T Bourgeois
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Many new molecular entities enter clinical development to evaluate potential therapeutic benefits for oncology patients. We characterized adult and pediatric development of the set of new molecular entities that started clinical testing in 2010-2015 worldwide. Methods We extracted data from AdisInsight, an extensive database of global pharmaceutical development, and the FDA.gov website. We followed the cohort of new molecular entities initiating first-in-human phase I clinical trials in 2010-2015 to the end of 2020. For each new molecular entity, we determined whether it was granted US Food and Drug Administration (FDA) approval, studied in a trial open to pediatric enrollment, or stalled during development. We characterized the cumulative incidence of these endpoints using statistical methods for censored data. Results The 572 new molecular entities starting first-in-human studies in 2010-2015 were studied in 6142 trials by the end of 2020. Most new molecular entities were small molecules (n = 316, 55.2%), antibodies (n = 148, 25.9%), or antibody-drug conjugates (n = 44, 7.7%). After a mean follow-up of 8.0 years, 173 new molecular entities did not advance beyond first-in-human trials, and 39 were approved by the FDA. New molecular entities had a 10.4% estimated probability (95% confidence interval = 6.6% to 14.1%) of being approved by the FDA within 10 years of first-in-human trials. After a median of 4.6 years since start of first-in-human trials, 67 (11.7%) new molecular entities were tested in trials open to pediatric patients, and 5 (0.9%) were approved for pediatric indications. Conclusions More efficient clinical development strategies are needed to evaluate new cancer therapies, especially for children, and incorporate approaches to ensure knowledge gain from investigational products that stall in development.
Revisiting the role of mesenchymal stem cells in tuberculosis and other infectious diseases
Authors: Annu Devi, Isha Pahuja, Shashi Prakash Singh, Akanksha Verma, Debapriya Bhattacharya, Ashima Bhaskar, Ved Prakash Dwivedi, Gobardhan Das
Journal: Cellular and Molecular Immunology (2023)

Mesenchymal stem cells (MSCs) play diverse roles ranging from regeneration and wound healing to immune signaling. Recent investigations have indicated the crucial role of these multipotent stem cells in regulating various aspects of the immune system. MSCs express unique signaling molecules and secrete various soluble factors that play critical roles in modulating and shaping immune responses, and in some other cases, MSCs can also exert direct antimicrobial effects, thereby helping with the eradication of invading organisms. Recently, it has been demonstrated that MSCs are recruited at the periphery of the granuloma containing Mycobacterium tuberculosis and exert "Janus"-like functions by harboring pathogens and mediating host protective immune responses. This leads to the establishment of a dynamic balance between the host and the pathogen. MSCs function through various immunomodulatory factors such as nitric oxide (NO), IDO, and immunosuppressive cytokines. Recently, our group has shown that M.tb uses MSCs as a niche to evade host protective immune surveillance mechanisms and establish dormancy. MSCs also express a large number of ABC efflux pumps; therefore, dormant M.tb residing in MSCs are exposed to a suboptimal dose of drugs. Therefore, it is highly likely that drug resistance is coupled with dormancy and originates within MSCs. In this review, we discussed various immunomodulatory properties of MSCs, their interactions with important immune cells, and soluble factors. We also discussed the possible roles of MSCs in the outcome of multiple infections and in shaping the immune system, which may provide insight into therapeutic approaches using these cells in different infection models.
Decoding enhancer complexity with machine learning and high-throughput discovery
Authors: Gabrielle D Smith, Wan Hern Ching, Paola Cornejo-Páramo, Emily S Wong
Journal: Genome biology (2023)

Enhancers are genomic DNA elements controlling spatiotemporal gene expression. Their flexible organization and functional redundancies make deciphering their sequence-function relationships challenging. This article provides an overview of the current understanding of enhancer organization and evolution, with an emphasis on factors that influence these relationships. Technological advancements, particularly in machine learning and synthetic biology, are discussed in light of how they provide new ways to understand this complexity. Exciting opportunities lie ahead as we continue to unravel the intricacies of enhancer function.
Genetic basis of geographical differentiation and breeding selection for wheat plant architecture traits
Authors: Yangyang Liu, Kuocheng Shen, Changbin Yin, Xiaowan Xu, Xuchang Yu, Botao Ye, Zhiwen Sun, Jiayu Dong, Aoyue Bi, Xuebo Zhao, Daxing Xu, Zhonghu He, Xueyong Zhang, Chenyang Hao, Jianhui Wu, Ziying Wang, He Wu, Danni Liu, Lili Zhang, Liping Shen, Yuanfeng Hao, Fei Lu, Zifeng Guo
Journal: Genome biology (2023)

Abstract Background Plant architecture associated with increased grain yield and adaptation to the local environments is selected during wheat ( Triticum aestivum ) breeding. The internode length of individual stems and tiller length of individual plants are important for the determination of plant architecture. However, few studies have explored the genetic basis of these traits. Results Here, we conduct a genome-wide association study (GWAS) to dissect the genetic basis of geographical differentiation of these traits in 306 worldwide wheat accessions including both landraces and traditional varieties. We determine the changes of haplotypes for the associated genomic regions in frequency in 831 wheat accessions that are either introduced from other countries or developed in China from last two decades. We identify 83 loci that are associated with one trait, while the remaining 247 loci are pleiotropic. We also find 163 associated loci are under strong selective sweep. GWAS results demonstrate independent regulation of internode length of individual stems and consistent regulation of tiller length of individual plants. This makes it possible to obtain ideal haplotype combinations of the length of four internodes. We also find that the geographical distribution of the haplotypes explains the observed differences in internode length among the worldwide wheat accessions. Conclusion This study provides insights into the genetic basis of plant architecture. It will facilitate gene functional analysis and molecular design of plant architecture for breeding.
The Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Oligometastatic Hormone-sensitive Prostate Cancer: A Post Hoc Analysis of ARCHES
Authors: Andrew J. Armstrong, Taro Iguchi, Arun A. Azad, Arnauld Villers, Boris Alekseev, Daniel P. Petrylak, Russell Z. Szmulewitz, Antonio Alcaraz, Neal D. Shore, Jeffrey Holzbeierlein, Francisco Gomez-Veiga, Brad Rosbrook, Fabian Zohren, Gabriel P. Haas, Georgia Gourgiotti, Nader El-Chaar, Arnulf Stenzl
Journal: European Urology (2023)

Few phase 3 studies have evaluated optimal systemic treatment strategies for patients with oligometastatic hormone-sensitive prostate cancer (HSPC), who may be at risk of undertreatment. To evaluate outcomes for patients with oligometastatic and polymetastatic HSPC treated with enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT. This was a post hoc analysis of data for 927 patients with nonvisceral metastatic HSPC in the ARCHES trial (NCT02677896). Patients were randomized 1:1 to enzalutamide (160 mg/d orally) plus ADT or placebo plus ADT with HSPC categorized as oligometastatic (1–5 metastases) or polymetastatic (≥6 metastases). The treatment effect on radiographic progression-free survival (rPFS), overall survival (OS), and secondary efficacy endpoints was evaluated in terms of the number of metastases. Safety was assessed. Cox proportional hazards models were used to generate hazard ratios (HRs). The Brookmeyer and Crowley method was used to generate 95% confidence intervals (CIs) for Kaplan-Meier median values. Enzalutamide plus ADT improved rPFS (HR 0.27, 95% CI 0.16–0.46; p < 0.001), OS (HR 0.59, 95% CI 0.40–0.87; p < 0.005), and secondary endpoints in patients with oligometastatic or polymetastatic disease (rPFS: HR 0.33, 95% CI 0.23–0.46; p < 0.001; OS: HR 0.55, 95% CI 0.41–0.74; p < 0.001). Safety profiles were generally similar across subgroups. Limitations include the small numbers of patients with fewer than three metastases. This post hoc analysis demonstrated the utility of enzalutamide, irrespective of metastatic burden or type of oligometastatic disease, and suggests that earlier treatment intensification with systemic potent androgen receptor inhibition is advantageous. This study considered two treatment options for metastatic hormone-sensitive prostate cancer in patients with one to five metastases or six or more metastases. Treatment with enzalutamide plus ADT improved survival and other outcomes over ADT alone, whether patients had few or many metastases.
A systematic review and meta-analysis of the effects of community use of oral nutritional supplements on clinical outcomes
Authors: A.L. Cawood, S.T. Burden, T. Smith, R.J. Stratton
Journal: Ageing Research Reviews (2023)

The impact of oral nutritional supplements (ONS) on patients with complications (disease related morbidity) requires further exploration. This systematic review included 44 randomised controlled trials (RCT) (29 RCT surgical, 15 RCT medical patients) examining the effect of ONS in community settings on the incidence of complications (n = 716, mean age 67 years, range 35-87). ONS (mean intake 588 kcal/day, range 125-1750; protein 22 g/day, range 0-54; mean energy from protein 22 %, range 0-54) were prescribed for a mean 74 days, range 5-365. Most RCT (77 %) reported fewer complications in the ONS group versus control. Meta-analysis (39 RCT) showed ONS consumption reduced complications including infections, pressure ulcers, wound and fracture healing (OR 0.68, 95 % CI 0.59,0.79; p<0.001). Results showed reductions when ONS were used in hospital and community settings (OR 0.72, 95 % CI 0.59,0.87; p = 0.001) or just in the community (OR 0.65, 95 % CI 0.52, 0.80; p<0.001). Reductions in complications were only seen with high ONS adherence ≥ 80 % (OR 0.63, 95 % CI 0.48,0.83; p = 0.001) and ready-to-drink ONS (OR 0.69, 95 % CI 0.60,0.81; p<0.001). This systematic review and meta-analysis show community-based use of ONS in addition to the diet substantially reduces the incidence of complications. The diversity of ONS, patient populations and complication outcomes within the trials included in this review mean further research is warranted.
Androgen Deprivation and Radiotherapy with or Without Docetaxel for Localized High-risk Prostate Cancer: Long-term Follow-up from the Randomized NRG Oncology RTOG 0521 Trial
Authors: Oliver Sartor, Theodore G. Karrison, Howard M. Sandler, Leonard G. Gomella, Mahul B. Amin, James Purdy, Jeff M. Michalski, Mark G. Garzotto, Nadeem Pervez, Alexander G. Balogh, George B. Rodrigues, Luis Souhami, M. Neil Reaume, Scott G. Williams, Raquibul Hannan, Christopher U. Jones, Eric M. Horwitz, Joseph P. Rodgers, Felix Y. Feng, Seth A. Rosenthal
Journal: European Urology (2023)

Intensification of therapy may improve outcomes for patients with high-risk localized prostate cancer. To provide long-term follow-up data from phase III RTOG 0521, which compared a combination of androgen deprivation therapy (ADT) + external beam radiation therapy (EBRT) + docetaxel with ADT + EBRT. High-risk localized prostate cancer patients (>50% of patients had Gleason 9–10 disease) were prospectively randomized to 2 yr of ADT + EBRT or ADT + EBRT + six cycles of docetaxel. A total of 612 patients were accrued, and 563 were eligible and included in the modified intent-to-treat analysis. The primary endpoint was overall survival (OS). Analyses with Cox proportional hazards were performed as prespecified in the protocol; however, there was evidence of nonproportional hazards. Thus, a post hoc analysis was performed using the restricted mean survival time (RMST). The secondary endpoints included biochemical failure, distant metastasis (DM) as detected by conventional imaging, and disease-free survival (DFS). After 10.4 yr of median follow-up among survivors, the hazard ratio (HR) for OS was 0.89 (90% confidence interval [CI] 0.70–1.14; one-sided log-rank p = 0.22). Survival at 10 yr was 64% for ADT + EBRT and 69% for ADT + EBRT + docetaxel. The RMST at 12 yr was 0.45 yr and not statistically significant (one-sided p = 0.053). No differences were detected in the incidence of DFS (HR = 0.92, 95% CI 0.73–1.14), DM (HR = 0.84, 95% CI 0.73–1.14), or prostate-specific antigen recurrence risk (HR = 0.97, 95% CI 0.74–1.29). Two patients had grade 5 toxicity in the chemotherapy arm and zero patients in the control arm. After a median follow-up of 10.4 yr among surviving patients, no significant differences are observed in clinical outcomes between the experimental and control arms. These data suggest that docetaxel should not be used for high-risk localized prostate cancer. Additional research may be warranted using novel predictive biomarkers. No significant differences in survival were noted after long-term follow-up for high-risk localized prostate cancer patients in a large prospective trial where patients were treated with androgen deprivation therapy + radiation to the prostate ± docetaxel.
The ethics of intervening in animal behaviour for conservation
Authors: Thom van Dooren, Catherine J. Price, Peter B. Banks, Oded Berger-Tal, Matthew Chrulew, Jane Johnson, Gabrielle Lajeunesse, Kate E. Lynch, Clare McArthur, Finn C.G. Parker, Myles Oakey, Benjamin J. Pitcher, Colleen Cassady St. Clair, Georgia Ward-Fear, Sam Widin, Bob B.M. Wong, Daniel T. Blumstein
Journal: Trends in Ecology & Evolution (2023)

Conservation behaviour is a growing field that applies insights from the study of animal behaviour to address challenges in wildlife conservation and management. Conservation behaviour interventions often aim to manage specific behaviours of a species to solve conservation challenges. The field is often viewed as offering approaches that are less intrusive or harmful to animals than, for example, managing the impact of a problematic species by reducing its population size (frequently through lethal control). However, intervening in animal behaviour, even for conservation purposes, may still raise important ethical considerations. We discuss these issues and develop a framework and a decision support tool, to aid managers and researchers in evaluating the ethical considerations of conservation behaviour interventions against other options.
LXR signaling controls homeostatic dendritic cell maturation
Authors: Victor Bosteels, Sandra Maréchal, Clint De Nolf, Sofie Rennen, Jonathan Maelfait, Simon J. Tavernier, Jessica Vetters, Evelien Van De Velde, Farzaneh Fayazpour, Kim Deswarte, Alexander Lamoot, Julie Van Duyse, Liesbet Martens, Cédric Bosteels, Ria Roelandt, Annelies Emmaneel, Sofie Van Gassen, Louis Boon, Gert Van Isterdael, Isabelle Guillas, Niels Vandamme, Doris Höglinger, Bruno G. De Geest, Wilfried Le Goff, Yvan Saeys, Kodi S. Ravichandran, Bart N. Lambrecht, Sophie Janssens
Journal: Science Immunology (2023)

Dendritic cells (DCs) mature in an immunogenic or tolerogenic manner depending on the context in which an antigen is perceived, preserving the balance between immunity and tolerance. Whereas the pathways driving immunogenic maturation in response to infectious insults are well-characterized, the signals that drive tolerogenic maturation during homeostasis are still poorly understood. We found that the engulfment of apoptotic cells triggered homeostatic maturation of type 1 conventional DCs (cDC1s) within the spleen. This maturation process could be mimicked by engulfment of empty, nonadjuvanted lipid nanoparticles (LNPs), was marked by intracellular accumulation of cholesterol, and was highly specific to cDC1s. Engulfment of either apoptotic cells or cholesterol-rich LNPs led to the activation of the liver X receptor (LXR) pathway, which promotes the efflux of cellular cholesterol, and repressed genes associated with immunogenic maturation. In contrast, simultaneous engagement of TLR3 to mimic viral infection via administration of poly(I:C)-adjuvanted LNPs repressed the LXR pathway, thus delaying cellular cholesterol efflux and inducing genes that promote T cell-mediated immunity. These data demonstrate that conserved cellular cholesterol efflux pathways are differentially regulated in tolerogenic versus immunogenic cDC1s and suggest that administration of nonadjuvanted cholesterol-rich LNPs may be an approach for inducing tolerogenic DC maturation.
Genetic mapping reveals <i>Pou2af2/</i> OCA-T1–dependent tuning of tuft cell differentiation and intestinal type 2 immunity
Authors: Marija S. Nadjsombati, Natalie Niepoth, Lily M. Webeck, Elizabeth A. Kennedy, Danielle L. Jones, Tyler E. Billipp, Megan T. Baldridge, Andres Bendesky, Jakob von Moltke
Journal: Science Immunology (2023)

Chemosensory epithelial tuft cells contribute to innate immunity at barrier surfaces, but their differentiation from epithelial progenitors is not well understood. Here, we exploited differences between inbred mouse strains to identify an epithelium-intrinsic mechanism that regulates tuft cell differentiation and tunes innate type 2 immunity in the small intestine. Balb/cJ (Balb) mice had fewer intestinal tuft cells than C57BL/6J (B6) mice and failed to respond to the tuft cell ligand succinate. Most of this differential succinate response was determined by the 50- to 67-Mb interval of chromosome 9 (Chr9), such that congenic Balb mice carrying the B6 Chr9 interval had elevated baseline numbers of tuft cells and responded to succinate. The Chr9 locus includes
Patient perspectives on the use of indwelling pleural catheters in malignant pleural effusions
Authors: Michael A Mitchell, Emilie Deschner, Inderdeep Dhaliwal, Michael Robinson, Pen Li, Chanel Kwok, Lorraine Cake, Emily Dawson, James Veenstra, Daniel Stollery, Ashley-Mae Gillson, Kayvan Amjadi
Journal: Thorax (2023)

Background Indwelling pleural catheters are an effective treatment option for patients with malignant pleural effusions. Despite their popularity, there remains a paucity of data on the patient experience and key patient-centred outcomes. Objective To investigate the experience of patients receiving an indwelling pleural catheter to better inform and identify potential areas for improvement in care. Methods This was a multicentre survey study at three academic, tertiary-care centres in Canada. Patients with a diagnosis of malignant pleural effusion who had an indwelling pleural catheter inserted were included. An adapted questionnaire specific to indwelling pleural catheters was used with responses recorded on a 4-point Likert scale. Patients completed the questionnaire in-person or by phone at 2-week and 3-month follow-up appointments. Results A total of 105 patients were enrolled in the study with 84 patients included in the final analysis. At the 2-week follow-up, patient-reported improvements in dyspnoea and quality of life from indwelling pleural catheter were high at 93% and 87%, respectively. The predominant issues identified were discomfort at time of insertion (58%), itching (49%), difficulty with sleeping (39%), discomfort with home drainage (36%) and the pleural catheter reminding patients of their disease (63%). Avoiding hospitalisation for the management of dyspnoea was important to 95% of patients. Findings were similar at 3 months. Conclusions Indwelling pleural catheters are an effective intervention to directly improve dyspnoea and quality of life but have important disadvantages for some; clinicians and patients should be aware of these when making an informed decision regarding treatment.
The impact of COVID-19 on antibiotic prescribing in primary care in England: Evaluation and risk prediction of appropriateness of type and repeat prescribing
Authors: Xiaomin Zhong, Alexander Pate, Ya-Ting Yang, Ali Fahmi, Darren M. Ashcroft, Ben Goldacre, Brian MacKenna, Amir Mehrkar, Sebastian C.J. Bacon, Jon Massey, Louis Fisher, Peter Inglesby, Kieran Hand, Tjeerd van Staa, Victoria Palin
Journal: Journal of Infection (2023)

This study aimed to predict risks of potentially inappropriate antibiotic type and repeat prescribing and assess changes during COVID-19.